1. Field of Invention
The present invention relates to a medicine of ligustrazine aromatic acid ether derivative for treating cardiovascular and cerebrovascular diseases, its preparation method, and medical compositions thereof, belongs to the field of pharmaceutical technology.
2. Description of Related Arts
Cardiovascular and cerebrovascular diseases are common diseases and frequently encountered diseases that harm people's health seriously, and has increasing incidence rate along with the aging of population. According to statistics, 16 million people die of various cardiovascular and cerebrovascular diseases each year, which is the first killer threatening human's health.
Thrombembolia is an important factor that causes cardiovascular and cerebrovascular diseases, coronary artery diseases and related ischemic complications may cause several clinic syndromes such as apoplexy, miocardial infarction and peripheral arterial disease, and the main reason is that the thrombus formed in the artery blocks the blood vessel and causes serious ischemia. Thromboembolic diseases, which has coronary artery thrombosis and cerebral thrombosis as core, has very high incidence rate and death rate in China. Therefore, it is the most popular research subject to prevent thrombus in the field of angiocardiopathy. At present, there are mainly three types of anticoagulants, platelet aggregation inhibitors and thrombolytic drugs for treating thrombotic diseases. Anticoagulants are generally drugs of low molecular weight including heparin drugs such as heparin sodium, coumarin drugs such as Warfarin, genetic recombined hirudin drugs such as Lepirudin and Bivalirudin, and polysaccharide sulfate. Platelet aggregation inhibitors can limit developing and embolizing of the thrombus in artery and vein, but can not prevent the artery thrombosis led by blood platelet. This type of drugs mostly have side effect of delayed hemorrhage. Thrombolytic drugs are generally biotechnical products, including streptokinase, urokinase, tissue-type plasminogen activator, duteplase, moteplase, and so on. This type of drugs can dissolve formed blood clot, so as to provide a fast and practical method for eliminating cardiovascular thrombus and cerebrovascular thrombus, establishing reperfusion of blood, saving dying cardiac muscle and brain tissue. However, this type of drugs have high requirement of purifying technology, and their products may have antigenicity to induce anaphylactic reaction. Some products may interfere coagulation function, and therefore has a danger of causing hemorrhage. Platelet aggregation inhibitors generally prevent forming and developing of thrombus by inhibiting aggregation of the platelet. Inhibitors of platelet aggregation can be classified into platelet activating factor (PAF) antagonist, inhibitor of thromboxane synthase and receptor antagonist, thrombin active site inhibitor, inhibitor of 10A factor, glycoprotein receptor IIb/IIIa (GPIIb/IIIa) antagonist, and so on. Besides Aspirin, Ticlopidine and Ozagrel, which are clinically used for years, this type of drugs include Abciximab, Argatroban, and Tirofiban, which has high bioactivity and relatively less side effect, but also has a danger of delayed hemorrhage. For overcoming the drawbacks of the foregoing drugs, it is still a hotspot of drug research to develop new-type, highly efficient and lowly toxic treating drugs for cardiovascular and cerebrovascular diseases. China has abundant natural resources of traditional Chinese medicinal materials, and it is of great theoretic significance and clinic application value to filter out components which can inhibit aggregation of platelet as lead compounds, and then process proper drug design and synthesization on the lead compounds by modern pharmacochemistry principles, so as to filter out drugs for treating thromboembolic diseases, which have better therapeutic effect, less side effects, higher bioavailability, and longer half time.
The design principle of the present invention is as follows:
Ozagrel and UK37248 are highly selective TXA2 synthetase inhibitors, and have very high antiplatelet aggregative activity, referring to Lizuka. K, Akahane. K, Momose. D, et al. Highly selective inhibitors of thromboxane synthetase. 1. Imidazole Derivatives. J. Med. Chem. 1981, 24(10): 1139-1148. Ozagrel and UK37248 can inhibit foming of cerebral thrombosis and cerebrovascular spasm, and are generally applied in treating acute cerebral infarction, coronary heart disease and angina, referring to Song Bo, Jiang Congqing, Cao chuanbin et al. Clinic research on treating unstable angina pectoris with sodium ozagrel. Chinese Journal of General Practitioners, 2006, 5(4): 255-256. And Wu Jinying. Clinical observation of 42 samples on treating acute cerebral infarction with sodium ozagrel. The structures of Ozagrel and UK37248 are as follows:

The dry rhizome of Ligusticum Wallichii Franch, which belongs to Apiaceae, is a kind of Chinese medicinal herb proved to be of great therapeutic effect by Chinese medical practice, has the function of promoting circulation of blood and Qi, eliminating bruise and relieving pain, and has been applied in treating ischemic cardiovascular and cerebrovascular diseases. Ligustrazine (Lig) is the main active component in Ligusticum Wallichii Franch, and its chemical name is 2,3,5,6-Tetramethylpyrazine, called Tetramethylpyrazine (TMP) for short. Its structure is as below:

According to the pharmacological research, Ligustrazine can dilate vessel, inhibit aggregation of platelet, prevent forming of thrombus, alleviate cerebral ischemia, referring to He Jing. Pharmacological effect and clinical application of Ligustrazine. Beijing medicine, 2005, 23: 31-32, and Wang yanping, Li Wenlan, Fan Yuqi. Progress of pharmacological effect of Ligustrazine. Orug Evaluation yao pin pingjia, 2006, 3(2): 144-150.
Ferulic acid is the active component of the Chinese medicinal herb including Angelica and Ligusticum Wallichii Franch. Its structure is as below:

According to the pharmacological research, Ferulic acid has the function of inhibiting aggregation of platelet, inhibiting releasing of 5-hydroxytryptamine from platelet, prevent forming of vein bypass thrombus, resisting atherosclerosis, anti-oxidation and enhancing immunologic function, referring to Ou shiyi, Bao Huiyan, Lan Zhidong. Progress of pharmacological effect of Ferulic acid and its derivatives. Journal of Chinese Medicinal Materials, 2001, 24(3): 220-221.
To searching for more effective ligustrazine compound, the present invention uses ligustrazine and ferulic acid as lead compounds, uses Ozagrel and UK37248 as model compounds according to the bioisosterism in pharmacochemistry, designs and synthesizes the Ligustrazine aromatic acid ether derivative according to the present invention, which is found to be highly efficient, lowly toxic and highly selective.